In vitro and in vivo inhibition of the host TRPC4 channel attenuates Zika virus infection.

Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death. Synopsis: ZIKV exhibits a high neurotropism and poses significant risks to the developing nervous system. We show that inhibition of the host TRPC4 channel or CaMKII impedes ZIKV propagation in human brain organoids and improves survival in a neonatal mouse model of ZIKV infection. ZIKV upregulates the expression of TRPC4 in host cells through the NS3-CaMKII-CREB pathway. Inhibition of the TRPC4 channel effectively disrupts the replication stage of the ZIKV life cycle. TRPC4 and CaMKII inhibitors successfully block proliferation and spread of ZIKV in human induced pluripotent stem cell (iPSC)-derived brain organoids. Treatment with TRPC4 and CaMKII inhibitors reduces seizures and improves survival rates in newborn mice infected with ZIKV. Thus, targeting TRPC4 holds promise as a potential approach for developing anti-ZIKV drugs, offering new treatment strategies for neurological dysfunction caused by ZIKV virus infection. ZIKV exhibits a high neurotropism and poses significant risks to the developing nervous system. We show that inhibition of the host TRPC4 channel or CaMKII impedes ZIKV propagation in human brain organoids and improves survival in a neonatal mouse model of ZIKV infection. [ABSTRACT FROM AUTHOR]